Abstract
Ewing sarcoma and osteosarcoma are two aggressive cancers that affect bones and soft tissues in children and adolescents. Despite multimodal therapy, patients with metastatic sarcoma have a poor prognosis, emphasizing a need for more effective treatment. We have shown previously that 2-methoxyestradiol (2-ME), an antitumoral compound, induces apoptosis in Ewing sarcoma cells through c-Jun NH(2)-terminal kinase (JNK) activation. In the present study, we provide evidence that 2-ME elicits macroautophagy, a process that participates in apoptotic responses, in a JNK-dependent manner, in Ewing sarcoma and osteosarcoma cells. We also found that the enhanced activation of JNK by 2-ME is partially regulated by p53, highlighting the relationship of JNK and autophagy to p53 signaling pathway. Furthermore, we showed that 2-ME up-regulates damage-regulated autophagy modulator (DRAM), a p53 target gene, in Ewing sarcoma cells through a mechanism that involves JNK activation. The silencing of DRAM expression reduced both apoptosis and autophagy triggered by 2-ME in Ewing sarcoma and osteosarcoma cells. Our results therefore identify JNK as a novel mediator of DRAM regulation. These findings suggest that 2-ME or other anticancer therapies that increase DRAM expression or function could be used to effectively treat sarcoma patients.
Highlights
Sarcomas are diverse tumors that arise from tissues of mesenchymal origin and affect bone and soft tissues [1]
Apoptosis triggered by 2-ME was significantly reduced following silencing of Beclin 1 and Atg7 (Fig. 1D). These results indicate that 2-ME enhances the autophagic flux in Ewing sarcoma cells, a process involved in apoptotic responses triggered by this compound
To determine the implication of damage-regulated autophagy modulator (DRAM) in the regulation of autophagy in Ewing sarcoma cells, we examined the abundance of the LC3-II form in 2-ME–treated cells in the presence or absence of DRAM expression by using DRAM-specific Small interfering RNAs (siRNA)
Summary
Sarcomas are diverse tumors that arise from tissues of mesenchymal origin and affect bone and soft tissues [1]. The resulting fusion proteins are presumed to be essential for maintaining oncogenesis of these tumors [6,7,8]. These tumors are clinically aggressive, highly metastatic, and typically more refractory to conventional therapy than are osteosarcomas. Many studies have focused on apoptosis because this process is the main mechanism by which anticancer drugs induce tumor cell killing [10,11,12]. Numerous studies have shown that apoptosis and autophagy share some common signaling pathways and are mutually regulated [15, 16]. JNK signals autophagy, at least in part, through the up-regulation of DRAM, which is a critical signal for the induction of apoptosis triggered by 2-ME
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